The microencapsulation of medicamentous substances is an established technique, which in particular permits the protection and the controlled administration of medicamentous substances having a short half-life in vivo. The resulting galenic form most often has the form of an injectable suspension of a very high efficiency.
Various methods of realization are described in the literature (see for example the patent Application EP No. 0052510). One of the most used methods of microencapsulation by phase separation can be described as follows:
(a) a biocompatible polymer is first dissolved in an organic solvent non-miscible with water (for example CH.sub.2 Cl.sub.2); PA0 (b) an aqueous solution of the selected medicamentous substance is then dispersed in the above-mentioned organic solution; PA0 (c) a said non-compatible polymer, such as a silicone oil, is then introduced under stirring into the dispersion obtained as described in (b) causing embrionic microcapsules to form by the deposition of the polymer initially dissolved on the dispersed medicamentous substance; PA0 (e) the microcapsules thus hardened are then filtered, washed and dried, or even sterilized according to usual techniques.
(d) the mixture obtained in (c) is then poured into an excess of an organic solvent non-miscible with water and non-solvent for the deposited polymer, such as for example heptane, thus causing the hardening of the microcapsules through the extraction of the initial organic solvent (for example CH.sub.2 Cl.sub.2) still contained in the mass of the deposited polymer;
The analyses which were carried out showed that the microcapsules dried to constant weight, still contained a high portion in weight of undesirable organic compounds, such as the heptane used during the step (d) hereabove. In a number of cases, the quantity of residual organic solvent turned out to be in fact equivalent or even higher, than that of the microencapsulated active principle (medicamentous substance), which strongly compromised any pharmaceutical application of such preparations.
Independently from the foregoing, it was found that aggregates of microcapsules were often obtained in the step of the phase separation, as well as during the hardening of the microcapsules, which results in important decreases in the yield, or even in the refusal of certain batches, which thus had become unusable.
According to the U.S. patent No. 4 166 800, the occurrence of such a phenomenon can be prevented by operating at temperatures comprised between -100.degree. and -40.degree. C. during the step of the phase separation, as well as during the hardening by the addition of a non-solvent of the polymer. Heptane is indicated as a choice non-solvent for the hardening.
To conduct industrially operations at such low temperatures is expensive and is a source of complications. Further, the use of organic solvents, such as for example heptane on an industrial scale presents a major drawback, i.e. the emission of large amounts of inflammable or even toxic vapours.